Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]([I:12])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].Cl.C(N(CC)CC)C.[CH3:21][C:22]([O:25][C:26](ON=C(C1C=CC=CC=1)C#N)=[O:27])([CH3:24])[CH3:23]>O.O1CCCC1>[C:22]([O:25][C:26]([C:4]1[C:3]([CH2:2][NH2:1])=[CH:11][CH:10]=[C:9]([I:12])[C:5]=1[C:6]([OH:8])=[O:7])=[O:27])([CH3:24])([CH3:23])[CH3:21]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCc1ccc(I)c(C(=O)O)c1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(CN)ccc(I)c1C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A suspension of 3-aminomethyl-6-iodobenzoic acid.circle-solid.HCl (8.0 g, 26 mmol) and triethylamine (8.7 g, 86 mmol) in 32 ml of H2O, was added to a solution of Boc-ON (8.0 g, 32 mmol) in 23 ml of tetrahydrofuran cooled to 0° C. The reaction mixture was stirred at room temperature for overnight, and the volatile compounds were removed by concentration under reduced pressure. The residue was diluted with H2O, washed with ether, acidified to pH 3 with 1N HCl, and extracted with ethyl acetate. The extracts were washed with H2O, brine, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. This material was triturated from ether to provide the title compound (5.7 g, 59%) as a white powder; mp 182° C. (dec);
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:10]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]3[CH2:42][O:41][CH2:40]3)=[CH:34][CH:33]=2)=[CH:11][C:12](=[O:31])[N:13]([CH2:15][CH2:16][C@@:17]([S:27]([CH3:30])(=[O:29])=[O:28])([NH:19][O:20]C2CCCCO2)[CH3:18])[CH:14]=1>C(Cl)Cl>[F:8][C:9]1[C:10]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]3[CH2:40][O:41][CH2:42]3)=[CH:34][CH:33]=2)=[CH:11][C:12](=[O:31])[N:13]([CH2:15][CH2:16][C@:17]([NH:19][OH:20])([S:27]([CH3:30])(=[O:29])=[O:28])[CH3:18])[CH:14]=1
Reactant: C[C@@](CCn1cc(F)c(-c2ccc(OC3COC3)cc2)cc1=O)(NOC1CCCCO1)S(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@](CCn1cc(F)c(-c2ccc(OC3COC3)cc2)cc1=O)(NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of 5-fluoro-1-{(3R)-3-(methylsulfonyl)-3-[(tetrahydro-2H-pyran-2-yloxy)amino]butyl}-4-[4-(oxetan-3-yloxy)phenyl]pyridin-2(1H)-one (164 mg, 0.304 mmol) in DCM (10 mL). The reaction was allowed to stir at rt overnight and then concentrated under vacuum. The residue was re-dissolved in dichloromethane and n-heptane and concentrated again to afford the title compound as a solid. (113 mg, 82%). MS (LCMS) m/z 455.1 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.69 (s, 3H) 2.35 (ddd, J=13.66, 10.63, 5.17 Hz, 1H) 2.53-2.67 (m, 1H) 3.09 (s, 3H) 3.91 (ddd, J=12.98, 10.63, 5.27 Hz, 1H) 4.16-4.30 (m, 1H) 4.69 (dd, J=7.51, 4.78 Hz, 2H) 5.02 (t, J=6.73 Hz, 2H) 5.33 (t, J=5.46 Hz, 1H) 6.58 (d, J=7.42 Hz, 1H) 6.85-6.91 (m, 2H) 7.55 (dd, J=8.68, 1.85 Hz, 2H) 7.80 (d, J=6.24 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C:5]=2[S:4][CH:3]=1.CCOCC.C([Li])CCC.[C:29]1(=[O:33])[CH2:32][CH2:31][CH2:30]1>O.CCCCCC>[O:10]1[C:11]2[C:2]([C:29]3([OH:33])[CH2:32][CH2:31][CH2:30]3)=[CH:3][S:4][C:5]=2[CH2:6][NH:7][CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)csc2C1
Reactant: O=C1CCC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: OC1(c2csc3c2OCCNC3)CCC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
To a solution of tert-butyl 8-bromo-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (334 mg) obtained in Example 1, steps 1-3, and Et2O (10 mL) was added dropwise 1.6 N hexane solution of n-butyllithium (72.4 ml) at −78° C., and the mixture was stirred at −78° C. for 15 min. Cyclobutanone (0.0747 ml) was added, and the mixture was stirred at −78° C. for 1 hr. To the reaction mixture was added water (10 mL), and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent gradient; 0→50% ethyl acetate/hexane) to give the title compound (190 mg, 58.5%) as an oil.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[N:5]([C:13](=[O:15])[CH3:14])[C@@H:4]([CH3:16])[CH2:3]1.Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:13]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)[C@H:2]([NH:1][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=2)[CH2:3][C@@H:4]1[CH3:16])(=[O:15])[CH3:14]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 200 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a mixture of 1-((2S,4R)-4-amino-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 7) (2.28 g, 8.05 mmol) and 6-chloronicotinonitrile (2.231 g, 16.10 mmol) was added NMP (20 ml) and the mixture treated with DIPEA (4.22 ml, 24.16 mmol). The mixture was split between 2 flasks and each flask was flushed with nitrogen, sealed and stirred under microwave irradiation at 200° C. for 2 h. The reaction mixtures were combined and partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (×4) and the combined organic layers were washed with water (×3), then brine and were dried (MgSO4) filtered and concentrated in vacuo. The brown solid residue was purified by chromatography (ethyl acetate/hexanes gradient) to give 6-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (1.940 g, 5.04 mmol, 62.5% yield) as a pale yellow foam. LCMS (HpH), Rt 1.02 min, MH+=386 (1 Br).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:17])[CH:3]=1.C([Li])CCC.C[O:24]B(OC)OC.Cl>O1CCCC1>[CH2:10]([O:9][C:5]1[C:4]([CH3:17])=[CH:3][C:2]([OH:24])=[CH:7][C:6]=1[Cl:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(Br)cc(Cl)c1OCc1ccccc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(O)cc(Cl)c1OCc1ccccc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
Then, 40 g of 4-bromo-6-chloro-2-methyl-1-benzyloxybenzene was dissolved in 400 ml of tetrahydrofuran, followed by stirring at -70° C., to which 76 ml of n-butyl lithium solution (in hexane, 1.69 mol/liter) was added dropwise, followed by further stirring at -70° C. for 2 hours. To this reaction mixture was added dropwise a solution of 13.3 g of trimethoxyborane dissolved in 50 ml of tetrahydrofuran. Then, the reaction mixture was stirred for 1 hours, while warming to room temperature, and 100 ml of 10% aqueous hydrochloric acid solution was added in small portions, followed by stirring for 20 minutes. The tetrahydrofuran layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated. The residue was mixed with 200 ml of toluene, and heated at 70° C. under stirring, to which 36 ml of 30% aqueous hydrogen peroxide solution was added dropwise. After heating under reflux for 1 hour, the reaction mixture was washed once with water, twice with 10% aqueous ammonium ferrous sulfate solution, and once with water, followed by phase separation. The toluene layer was dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 29 g of 4-benzyloxy-3-chloro-5-methylphenol (91% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][CH:17]=[O:18])[C:11]=1[OH:19].CN(C=O)C.Br[CH2:27][CH2:28][CH2:29]Cl>O.C(OCC)(=O)C>[CH3:7][O:8][C:9]([C:10]1[C:11]2[O:19][CH2:29][CH2:28][CH2:27][N:16]([CH:17]=[O:18])[C:12]=2[CH:13]=[CH:14][CH:15]=1)=[O:20]
Reactant: COC(=O)c1cccc(NC=O)c1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1OCCCN2C=O
Temperature: 120 °C
Yield: 75.7 %

Procedure:
Potassium carbonate was ground and flame dried prior to each use. 3-formylamino-2-hydroxy-benzoic acid methyl ester compound (1.952 grams, 10 mmol) and potassium carbonate (2.764 grams, 20 mmol, 2 eq.) were placed in a flask together with 100 mL of anhydrous DMF. Heated to 120° C. for 1 hour. 1-bromo-3-chloropropane (1 mL, 10 mmol, 1 eq.) was added to the reaction mixture in several portions at 120° C. and the reaction heated for an additional 3 hours. The reaction was monitored on TLC (ethyl acetate). After cooling, the reaction mixture was stripped to a minimal volume, diluted with water and extracted three times with ethyl acetate. The combined organic portions were washed with water, brine and dried over magnesium sulfate. Filtration and solvent removal afforded crude product as a thick brown syrup (1.78 grams) which was chromatographed on silica gel using 30% ethyl acetate in hexane as eluent. The product was obtained in 67% yield as light yellow solid. M+236.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1[C:39]1([NH2:42])[CH2:41][CH2:40]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:34]6[N:35]=[CH:36][CH:37]=[CH:38][N:33]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NC1(c2ncccn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncccn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(pyrimidin-2-yl)cyclopropanamine (0.074 g, 0.55 mmol, 1.2 eq), HOBT (0.105 g, 0.77 mmol, 1.7 eq), EDC.HCl (0.0.158 g, 0.82 mmol, 1.8 eq), in DCM at ambient temperature and under nitrogen atmosphere was added diisopropylehtylamine (0.297 g, 2.2 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and preparative HPLC. Yield: 0.055 g (45%). 1HNMR (400 MHz, DMSO-d6): δ 1.43-1.44 (m, 2H), 1.59-1.62 (m, 2H), 2.31 (s, 3H), 2.81-2.82 (d, 3H, J=4.56 Hz), 4.01 (s, 3H), 7.17 (s, 1H), 7.26-7.29 (t, 1H, J=4.8 Hz), 7.33-7.36 (dd, 1H, J=8.4, 4 Hz), 7.38-7.43 (t, 2H, J=8.8 Hz), 7.50-7.51 (d, 1H, J=1.6 Hz), 7.72-7.76 (m, 2H), 7.97-8.01 (m, 2H), 8.48-8.49 (d, 1H, J=4.4 Hz), 8.7 (d, 2H, J=4.8 Hz), 8.87 (s, 1H). LCMS: (ES+) m/z=551.2 (M+H) Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH Flow: 1 mL/Min
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].[Cl-].[NH4+].CC[N:16](CC)CC>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH2:16])=[O:6]
Reactant: CCN(CC)CC
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(N)=O)cc1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-Bromo-4-methylbenzoic acid (1.5 g, 7.0 mmol) in thionyl chloride (10 mL) was heated to 80° C. for 1 h. The solvent was removed in vacuo and the residue was dissolved in DCM (16 mL) at 0° C. under argon before adding ammonium chloride (410 mg, 7.7 mmol) and Et3N (2.43 mL, 17.4 mmol). The reaction was stirred at 0° C. for 15 min then allowed to warm to rt over 16 h. The solvent was removed in vacuo and the mixture partitioned between EtOAc (120 mL) and 1M NaOH (60 mL). The organic phase was washed with 1M NaOH (60 mL), brine (60 mL) and dried (MgSO4). The solvent was removed in vacuo. Trituration with ether and then MeOH gave the title compound: RT=2.78 min; m/z (ES+)=214.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16](O)=[O:17])[CH:12]=2)[CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:67][CH2:68][CH2:69][NH:70][C:71](=[O:77])[O:72][C:73]([CH3:76])([CH3:75])[CH3:74]>CN(C=O)C.O>[F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:67][CH2:68][CH2:69][NH:70][C:71](=[O:77])[O:72][C:73]([CH3:75])([CH3:74])[CH3:76])=[O:17])[CH:12]=2)[CH:6]=1
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)c2)c1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCNC(=O)OC(C)(C)C)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (Example 13) (300 mg, 0.67 mmol), HATU (281 mg, 0.74 mmol) and N,N-diisopropylethylamine (190 mg, 1.47 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of tert-butyl (2-aminoethyl)carbamate (160 mg, 1.0 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl {2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]ethyl}carbamate as white solid. Yield: 395 mg, 100%.
Reaction SMILES: C[CH:2]([CH2:6][C:7]1[O:8][C:9]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:11]=1)[C:3](O)=[O:4].[NH3:29]>CO>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[N:11]=[C:7]([CH2:6][CH2:2][C:3]([NH2:29])=[O:4])[O:8][C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CC(Cc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)o1)C(=O)O
Reactant: N
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2oc(CCC(N)=O)nc2-c2ccc(F)cc2)cc1

Procedure:
3-[4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)oxazol-2-yl]propanamide was prepared by treating methyl 3-[4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)oxazol-2-yl]propanoic acid, (Example 12) with excess ammonia in methanol for 5 days. Melting point: 193°-195° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.CC1C=CC2C(=O)OC(=O)[NH:29]C=2C=1>>[NH:16]1[CH2:20][CH2:19][N:29]=[C:17]1[CH2:18][NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10]
Reactant: C1CCNC1
Reactant: Cc1ccc(C(=O)N2CCCC2)c(N)c1
Reactant: Cc1ccc2c(=O)oc(=O)[nH]c2c1
Product: Cc1ccc(C(=O)N2CCCC2)c(NCC2=NCCN2)c1

Procedure:
(2-Amino-4-methylphenyl)(1-pyrrolidinyl)methanone (prepared from pyrrolidine and 7-methyl-2H-3,1-benzoxazine-2,4(1H)-dione using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give {2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]-4-methylphenyl}(1-pyrrolidinyl)methanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(N)ccc1-n1ccnc1
Yield: 84.2 %

Procedure:
A solution of 350 mg (1.6 mmol) 1-(2-methoxy-4-nitro-phenyl)-1H-imidazole and 1873 mg (8.3 mmol) stannous dichloride in ethyl acetate (5 ml) and ethanol (2.5 ml) were heated to 70° for 35 minutes. The reaction was poured onto water/ice and neutralized with an aqueous solution of sodium hydrogen carbonate. It was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate, filtered and the solvent was evaporated under reduced pressure to yield 255 mg (84%) 3-methoxy-4-(imidazol-1-yl)-phenylamine as a brown solid. MS ISP (m/e): 190.0 (100) (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([CH3:39])[C:29]=1[N:30]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[N:31]1)[O:6][CH:7]([C:11]1[CH:26]=[CH:25][C:14]([C:15]([NH:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[O:16])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10].O1CCCC1.CO.[OH-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([CH3:39])[C:29]=1[N:30]1[CH:34]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:32]=[N:31]1)[O:6][CH:7]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[CH:25][CH:26]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCC(Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(OC)c1)c1ccc(C(=O)NCCC(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CCCC(Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(OC)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.5 %

Procedure:
To a flask containing ethyl 3-(4-(1-(3-methoxy-5-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoate (37.0 mg, 0.0700 mmol) was added tetrahydrofuran (0.170 mL), methanol (0.170 mL), and 1 N sodium hydroxide (0.170 mL, 0.170 mmol) was then added. The suspension was stirred at room temperature for 18 hours. The reaction was quenched with 1 N hydrochloric acid to pH 2 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give crude material. The crude material was azeotrophed three times with methylene chloride and then dried in vacuo for 18 h to provide (+/−)-3-(4-(1-(3-methoxy-5-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzamido) propanoic acid (26.0 mg, 74%) as a solid. 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.66 (s, 1H), 7.39 (d, J=8.2 Hz, 2H), 6.88 (t, J=6.0 Hz, 1H), 6.41-6.21 (m, 2H), 5.17 (dd, J=7.7, 5.2 Hz, 1H), 3.75-3.65 (m, 2H), 3.63 (s, 3H), 2.66 (t, J=5.9 Hz, 2H), 2.04-1.93 (m, 1H), 1.89 (s, 3H), 1.86-1.74 (m, 1H), 1.62-1.35 (m, 2H), 0.96 (t, J=7.4 Hz, 3H). MS (M+1): 520.4.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][CH2:5][C:6]1([C:11](OC)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH3:16][O:15][CH:3]([O:2][CH3:1])[CH2:4][CH2:5][C:6]1([CH2:11][OH:12])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C1(CCC(OC)OC)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COC(CCC1(CO)CCCC1)OC
Reaction time: 4 h

Procedure:
A solution of 0.25 mol of the compound prepared in Stage A of Example 10 in 200 ml of ether is added dropwise to a suspension, stirred at 0° C., of 0.25 mol of lithium aluminum hydride in 200 ml of ether. When the addition is complete, the reaction medium is allowed to return to room temperature, and is then stirred for 4 hours at this temperature before being hydrolyzed by adding 20 ml of water. The salts are filtered off and washed twice with ether, and the filtrate is dried and concentrated.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:22]NC(=O)C)[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:5]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])[C:6]=1[Br:7].O(Cl)[Cl:28].O>C(Cl)Cl>[Br:1][C:2]1[N:3]([CH2:22][Cl:28])[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:5]([S:8]([C:11]([F:14])([F:12])[F:13])(=[O:10])=[O:9])[C:6]=1[Br:7]
Reactant: ClOCl
Reactant: CC(=O)NCn1c(Br)c(Br)c(S(=O)(=O)C(F)(F)F)c1-c1ccc(Cl)cc1
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1c(Br)c(Br)n(CCl)c1-c1ccc(Cl)cc1)C(F)(F)F
Reaction time: 8 h

Procedure:
N-{{2,3-Dibromo-5-(p-chlorophenyl)-4-[(trifluoromethyl)sulfonyl]pyrrol-1-yl}methyl}acetamide (4.5 g, 0.00835 mol) is added to phosphoros oxychloride (15 mL). The reaction mixture is refluxed for 31/2 hours, poured into water, stirred overnight and filtered to obtain a solid. The solid is dissolved into methylene chloride and the solution is dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title product as a yellow solid (3.8 g, mp 153°-156° C.) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3](=O)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1>C(O)C.Cl>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:5]([C:6]3[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=3)[CH2:4][C:3]([C:2]([F:18])([F:17])[F:1])=[N:27]2)=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)c1ccc(/C=C/C(=O)C(F)(F)F)cc1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(N2N=C(C(F)(F)F)CC2c2ccc(S(C)(=O)=O)cc2)cc1
Yield: 32 %

Procedure:
In a flask with an inert atmosphere (E)-1,1,1-trifluoro-4-(4-methylsulphonylphenyl)-3-butene-2-one (prepared according to the method E-1) (1.83 g, 6.58 mmoles) and 4-methylphenylhydrazine chlorohydrate (1.04 g, 6.58 mmoles) are dissolved in 50 ml de ethanol. A few drops of hydrochloric acid are added, and the mixture refluxed under an inert atmosphere for 4 days. The mixture is cooled and the product crystallised. The solution is filtered and the product recrystallised from ethanol. 4,5-dihydro-1-(4-methylphenyl]-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole (0.8 g, yield: 32%) is obtained in the form of a solid with a melting point of 140-3° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:9]([C:20]([F:23])([F:22])[F:21])[CH:8]=1.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.O>C1COCC1>[CH3:19][O:18][CH2:17][CH2:16][O:15][CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([B:24]([OH:29])[OH:25])=[CH:8][C:9]=1[C:20]([F:23])([F:22])[F:21]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCCOCOc1ccc(Br)cc1C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCCOCOc1ccc(B(O)O)cc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (2.5M in hexane, 91.2 ml) was added dropwise to a solution of 4-bromo-1-(2-methoxy-ethoxymethoxy)-2-trifluoromethyl-benzene (30 g) in dry THF (335 ml) at −78° C. under nitrogen atmosphere. The mixture was then stirred at −78° C. for another 30 minutes. Triisopropyl borate (101 ml) was then added slowly at −78° C. under nitrogen, the mixture was then allowed to slowly warm up to room temperature and stirred at this temperature overnight. After adding water (300 ml), the mixture was extracted with ethyl acetate (300 ml×3). The combined organic layers were dried over sodium sulphate. After removal of solvent under reduced pressure, the residue was columned on silica gel using DCM-MeOH as eluant to give 4-(2-methoxy-ethoxymethoxy)-3-trifluoromethyl-phenyl-boronic acid (14.4 g).